This invention relates to amino acid-containing therapeutic compounds.
The endogenous analgesic oligopeptides known as the enkephalins are known to be cleaved by an endopeptidase referred to as enkephalinase. Enkephalinase is known to be inhibited by a number of substances, including "the dipeptide Phe-Ala and the thiol derivative Thiorphan"; Llorens et al. (1981) Eur. J. Pharm. 69, 113. Thiorphan ((DL-3-mercapto-2-benzylpropanoyl) glycine), described in U.S. Pat. No. 3,008,601, "protects the enkephalins from the action of enkephalinase in vitro in nanomolar concentration and in vivo after either intracerebroventricular or systemic administration"; Roques et al. (1980) Nature 288, 5788. It was reported in Coletti-Prieviero et al. (1982) B.B.R.C. 107, 465 that amino acid hydroxamates containing, respectively, tryptophan, tyrosine, phenylalamine, arginine, and alanine inhibited enkephalin in vitro. The presence of both enkephalinase and enkephalin receptors has been demonstrated in many tissues in addition to the brain. For example, enkephalin receptors have been found in dog intestine; Oka, TIPS (1981), and enkephalinases have been found in salivary glands, thyroid tissue, lung, kidney, and adrenal tissue. A low level of enkephalins, in addition to being associated with hyperalgesia, has been implicated in mental depression; Emrich in Typical and Atypical Antidepressants: Clinical Practice, Costa et al., eds. (1982).